3'-Hydroxypterostilbene Inhibits 7,12-Dimethylbenz[a]anthracene (DMBA)/12-O-Tetradecanoylphorbol-13-Acetate (TPA)-Induced Mouse Skin Carcinogenesis

Pei-Sheng Lee; Yi-Shiou Chiou; Pin-Yu Chou; Kalyanam Nagabhushanam; Chi-Tang Ho; Min-Hsiung Pan

doi:10.1016/j.phymed.2020.153432

3'-Hydroxypterostilbene Inhibits 7,12-Dimethylbenz[a]anthracene (DMBA)/12-O-Tetradecanoylphorbol-13-Acetate (TPA)-Induced Mouse Skin Carcinogenesis

Phytomedicine. 2021 Jan:81:153432. doi: 10.1016/j.phymed.2020.153432. Epub 2020 Dec 3.

Authors

Pei-Sheng Lee¹, Yi-Shiou Chiou², Pin-Yu Chou¹, Kalyanam Nagabhushanam³, Chi-Tang Ho⁴, Min-Hsiung Pan⁵

Affiliations

¹ Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan.
² Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan; Tsinghua Berkeley Shenzhen Institute (TBSI), Tsinghua University, Shenzhen, China.
³ Sabinsa Corporation, East Windsor, NJ, USA.
⁴ Department of Food Science, Rutgers University, New Brunswick, New Jersey, USA.
⁵ Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan. Electronic address: mhpan@ntu.edu.tw.

PMID: 33310310
DOI: 10.1016/j.phymed.2020.153432

Abstract

Background: A natural pterostilbene analogue isolated from the herb Sphaerophysa salsula, 3'-hydroxypterostilbene (HPSB), exhibits antiproliferative activity in several cancer cell lines; however, the inhibitory effects of HPSB on skin carcinogenesis remains unclear.

Purpose: The aim of this study was to evaluate the inhibitory effects of HPSB on two-stage skin carcinogenesis in mice and its potential mechanism.

Study design and methods: This study investigated the anti-inflammatory and anti-tumor effects of HPSB in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated acute skin inflammation and 7,12-dimethylbenz[a]anthracene (DMBA)/TPA-induced two-stage skin carcinogenesis model. In addition, the effects of HPSB on the modulation of the phase I and phase II metabolizing enzymes in the DMBA-induced HaCaT cell model were investigated.

Results: The results provide evidence that topical treatment with HPSB significantly inhibits TPA-induced epidermal hyperplasia and leukocyte infiltration through the down-regulation of cyclooxygenase-2 (COX-2), matrix metalloprotein-9 (MMP-9), and ornithine decarboxylase (ODC) protein expression in mouse skin. Furthermore, HPSB suppresses DMBA/TPA-induced skin tumor incidence and multiplicity via the inhibition of proliferating cell nuclear antigen (PCNA), Cyclin B1 and cyclin-dependent kinase 1 (CDK1) expression in the two-stage skin carcinogenesis model. In addition, pretreatment with HPSB markedly reduces DMBA-induced cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) gene expression in human keratinocytes; however, HPSB does not significantly affect the gene expression of the phase II enzymes.

Conclusion: This is the first study to show that topical treatment with HPSB prevents mouse skin tumorigenesis. Overall, our study suggests that natural HPSB may serve as a novel chemopreventive agent capable of preventing carcinogen activation and inflammation-associated tumorigenesis.

Keywords: 12-O-Tetradecanoylphorbol-13-acetate; 3′-hydroxypterostilbene; 7,12-Dimethylbenz[a]anthracene; Anti-inflammation; Chemoprevention.

MeSH terms

9,10-Dimethyl-1,2-benzanthracene / toxicity*
Administration, Topical
Animals
Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Anticarcinogenic Agents / administration & dosage
Anticarcinogenic Agents / pharmacology*
Carcinogens / toxicity
Cyclooxygenase 2 / metabolism
Drug Eruptions / etiology
Drug Eruptions / prevention & control
Female
Gene Expression Regulation / drug effects
Humans
Keratinocytes / drug effects
Keratinocytes / pathology
Mice
Mice, Inbred ICR
Ornithine Decarboxylase / metabolism
Skin Neoplasms / chemically induced
Skin Neoplasms / pathology
Skin Neoplasms / prevention & control*
Stilbenes / administration & dosage
Stilbenes / pharmacology*
Tetradecanoylphorbol Acetate / toxicity*

Substances

3'-hydroxypterostilbene
Anti-Inflammatory Agents, Non-Steroidal
Anticarcinogenic Agents
Carcinogens
Stilbenes
9,10-Dimethyl-1,2-benzanthracene
Ptgs2 protein, mouse
Cyclooxygenase 2
Ornithine Decarboxylase
Tetradecanoylphorbol Acetate